The immune system comprises a highly interactive complex of tissues, cell types, and soluble factors. Recently, it has been suggested that several diseases and immune disorders may be associated with imbalances among certain components of the immune system, particularly cytokines, e.g. Mosmann et al, Ann. Rev. Immunol., Vol. 7, pgs. 145-173 (1989); Cher et al, J. Immunol., Vol. 138, pgs. 3688-3694 (1987); Mosmann et al, Immunol. Today, Vol. 8, pgs. 223-227 (1987); and Heinzel et al, J. Exp. Med., Vol. 169, pgs. 59-72 (1989).
For example, a large body of evidence suggests that excessive production of gamma interferon (IFN-.gamma.) is responsible for major histocompatibility complex (MHC) associated autoimmune diseases, Hooks et al, New England J. Med., Vol. 301, pgs. 5-8 (1979) (elevated serum levels of IFN-.gamma. correlated with autoimmunity); Basham et al, J. Immunol., Vol. 130, pgs. 1492-1494 (1983) (IFN-.gamma. can increase MHC gene product expression); Battazzo et al, Lancet, pgs. 1115-1119 (Nov. 12, 1983) (aberrant MHC gene product expression correlated with some forms of autoimmunity); Hooks et al, Ann. N.Y. Acad. Sci., Vol., pgs. 21-32 (1980) (higher IFN-.gamma. levels correlated to greater severity of disease in SLE patients, and histamine-release enhancing activity of interferon can be inhibited by anti-interferon sera); Jacob et al, J. Exp. Med., Vol. 166, pgs. 798-803 (1987) (amelioration and delay of onset of disease conditions in mouse models of systemic lupus erythematosus by blocking anti-IFN-.gamma. monoclonal antibodies); and Iwatani et al, J. Clin. Endocrin. and Metabol., Vol. 63, pgs. 695-708 (1986) (anti-IFN-.gamma. monoclonal antibody eliminated the ability of leucoagglutinin-stimulated T cells to induce HLA-DR expression). It has been hypothesized that excess IFN-.gamma. causes the inappropriate expression of MHC gene products which, in turn, causes autoimmune reactions against the tissues whose cells are inappropriately expressing the MHC products and displaying autoantigens in the context of the products. Thus, it has been suggested that reducing IFN-.gamma. levels in autoimmune patients, e.g. by administering IFN-.gamma. antagonists, could have beneficial effects, e.g. McDevitt, Clin. Res., Vol. 34, pgs. 163-175 (1985).
In addition to the above evidence, IFN-.gamma. may also play a role in allergy by its ability to increase the number and density of Fc.epsilon. receptors on monocytes, it has been implicated in the pathogenesis of sarcoidosis and psoriasis, and it is believed to augment cell-mediated immunity, which plays a major role in tissue rejection in allogenic transplant patients.
In view of the above, the availability of compounds capable of reducing IFN-.gamma. levels would be highly advantageous for treatment of diseases associated with inappropriate immune responses, such as some parasitic diseases, allergy, and MHC associated immune disorders, including rheumatoid arthritis, systemic lupus erythematosus (SLE), myasthenia gravis, insulin-dependent diabetes mellitus, thyroiditis, and the like.